Young gay and bisexual men (YGBM) disproportionately experience depression, anxiety, and substance use problems and are among the highest risk group for HIV infection in the U.S. Diverse methods locate the source of these health disparities in YGBM's exposure to minority stress. In fact, minority stress, psychiatric morbidity, substance use, and HIV risk fuel each other, forming a synergistic threat to YGBM's health. Yet no intervention addresses minority stress, mental health and substance use problems, or their joint impact on HIV risk in this population. Recently discovered minority stress pathways offer clear targets for improving YGBM's mental health and reducing HIV risk. Some of these processes are cognitive and affective in nature, such as internalized homophobia and rejection schemas, whereas others are characterized by behavioral avoidance, such as sexual orientation concealment, unassertiveness, and impulsivity. Strong evidence suggests that each of YGBM's co-occurring health risks is rooted in these minority stress pathways. Preliminary Studies. ESTEEM (Effective Skills to Empower Effective Men) is a 10-session skills-building intervention designed to reduce YGBM's co-occurring health risks by addressing the underlying cognitive, affective, and behavioral pathways through which minority stress impairs health. We created ESTEEM (NIMH R34), by adapting a unified cognitive-behavioral protocol to promote minority stress coping among depressed / anxious and at-risk YGBM. ESTEEM aims to normalize the adverse impact of minority stress, reduce internalized homophobia and rejection schemas, and decrease YGBM's unhealthy avoidance tendencies (e.g., substance use during sex, condom use non-assertion). In a preliminary waitlist trial, ESTEEM significantly reduced YGBM's spectrum of related health threats, making it the first evidence-based intervention to simultaneously improve mental health, substance use, and sexual risk outcomes in YGBM. Methods. To determine (1) the efficacy of ESTEEM compared to community mental health treatment and HIV counseling and testing, (2) whether ESTEEM works through its hypothesized cognitive, affective, and behavioral minority stress processes, and (3) ESTEEM's cost-effectiveness in terms of improved mental health and HIV infections averted. Our primary outcome at baseline, 3-, 6-, and 12-months is protected sex, defined as condomless anal sex in the absence of PrEP or known undetectable viral load of HIV+ primary partners. Secondary outcomes include depression, anxiety, substance use, sexual compulsivity, and PrEP uptake-FDA-approved since our R34 pilot. Deploying stand-alone interventions for separate problems represents the current, but most costly, method of reducing YGBM's mental, behavioral, and sexual health problems. A single intervention that reduces YGBM's depression, anxiety, substance use, and HIV risk by reducing the common minority stress pathways across these problems represents an efficient, cost-effective alternative to currently isolated approaches, and holds great promise for reducing sexual orientation health disparities among young men.